tbuckley/cabot-search huggingface dataset:
Genomic Signatures of Mitonuclear Coevolution in Mammals
Authors: Ryan J Weaver, Samantha Rabinowitz, Kiley Thueson, Justin C Havird
Journal: Molecular Biology and Evolution (2022)

Abstract Mitochondrial (mt) and nuclear-encoded proteins are integrated in aerobic respiration, requiring co-functionality among gene products from fundamentally different genomes. Different evolutionary rates, inheritance mechanisms, and selection pressures set the stage for incompatibilities between interacting products of the two genomes. The mitonuclear coevolution hypothesis posits that incompatibilities may be avoided if evolution in one genome selects for complementary changes in interacting genes encoded by the other genome. Nuclear compensation, in which deleterious mtDNA changes are offset by compensatory nuclear changes, is often invoked as the primary mechanism for mitonuclear coevolution. Yet, direct evidence supporting nuclear compensation is rare. Here, we used data from 58 mammalian species representing eight orders to show strong correlations between evolutionary rates of mt and nuclear-encoded mt-targeted (N-mt) proteins, but not between mt and non-mt-targeted nuclear proteins, providing strong support for mitonuclear coevolution across mammals. N-mt genes with direct mt interactions also showed the strongest correlations. Although most N-mt genes had elevated dN/dS ratios compared to mt genes (as predicted under nuclear compensation), N-mt sites in close contact with mt proteins were not overrepresented for signs of positive selection compared to noncontact N-mt sites (contrary to predictions of nuclear compensation). Furthermore, temporal patterns of N-mt and mt amino acid substitutions did not support predictions of nuclear compensation, even in positively selected, functionally important residues with direct mitonuclear contacts. Overall, our results strongly support mitonuclear coevolution across ∼170 million years of mammalian evolution but fail to support nuclear compensation as the major mode of mitonuclear coevolution.
Biomarkers of asthma relapse and lung function decline in adults with spontaneous asthma remission: A population‐based cohort study
Authors: Daniel J. Tan, Caroline J. Lodge, Eugene Haydn Walters, Adrian J. Lowe, Dinh S. Bui, Gayan Bowatte, Rangi Kandane‐Rathnayake, Fahad M. Aldakheel, Bircan Erbas, Garun S. Hamilton, Paul S. Thomas, Mark Hew, Mimi L. K. Tang, Michael J. Abramson, Jennifer L. Perret, Shyamali C. Dharmage
Journal: Allergy (2022)

The extent to which biomarkers of asthma activity persist in spontaneous asthma remission and whether such markers are associated with future respiratory outcomes remained unclear. We investigated the association between sub-clinical inflammation in adults with spontaneous asthma remission and future asthma relapse and lung function decline.
Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming
Authors: Ting Zhao, Jianming Zeng, Yujie Xu, Zhongping Su, Yulong Chong, Tao Ling, Haozhe Xu, Hui Shi, Minggao Zhu, Qi Mo, Xiaoying Huang, Yingchang Li, Xiaoren Zhang, Hongbin Ni, Qiang You
Journal: Theranostics (2022)

Background: Chitinase-3-like protein 1 (CHI3L1) is overexpressed in various types of tumors, especially in glioma, and contributes to tumor progression. However, the definite role of CHI3L1 and involved pathway in glioma progression are not completely understood. Methods: CHI3L1 expression in human gliomas and its association with patient survival was determined using enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and public databases. Single-cell RNA-seq was used to characterize the landscape of tumor and myeloid cells. Human proteome microarray assay was applied to identify the binding partners of CHI3L1. Protein-protein interactions were analyzed by co-immunoprecipitation and cellular co-localization. The roles of CHI3L1 in glioma proliferation and invasion were investigated in tumor cell lines by gain- and loss- of function, as well as in vivo animal experiments. Results: CHI3L1 was up-regulated in all disease stages of glioma, which was closely related with tumor survival, growth, and invasion. CHI3L1 was primarily expressed in glioma cells, followed by neutrophils. Moreover, glioma cells with high expression of CHI3L1 were significantly enriched in NF-κB pathway. Pseudo-time trajectory analysis revealed a gradual transition from CHI3L1low to CHI3L1high glioma cells, along with the NF-κB pathway gradually reversed from inhibition to activation. Intriguingly, CHI3L1 binds to actinin alpha 4 (ACTN4) and NFKB1, and enhances the NF-κB signaling pathway by promoting the NF-κB subunit nuclear translocation in glioma cells. Further, CHI3L1 were released into the tumor microenvironment (TME) and interacted with CD44 expressed on tumor-associated macrophages to activate AKT pathway, thereby contributing to M2 macrophage polarization. In addition, CHI3L1 positively correlated to the expression of immune checkpoints, such as CD274 (PD-L1) and HAVCR2 (LAG3), which then remodeled the TME to an immunosuppressive phenotype. Conclusion: Our research revealed that CHI3L1 facilitated NF-κB pathway activation within glioma cells and reprogramed the TME, thereby serving as a promising therapeutic target for glioma.
Reexamining Social Determinants of Health Data Collection in the COVID-19 Era
Authors: Samyukta Mullangi, Emeline M. Aviki, Dawn L. Hershman
Journal: JAMA Oncology (2022)

This Viewpoint describes the association of various factors, including demographic factors, disease-related factors, and social determinants of health, with cancer treatment delays among a cohort of patients across multiple sites who had all tested positive for SARS-CoV-2.
Hypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors: Targeting Genetically Driven Tumor Hypoxia
Authors: Rodrigo A Toledo, Camilo Jimenez, Gustavo Armaiz-Pena, Carlota Arenillas, Jaume Capdevila, Patricia L M Dahia
Journal: Endocrine Reviews (2022)

Tumors driven by deficiency of the VHL gene product, which is involved in degradation of the hypoxia-inducible factor subunit 2 alpha (HIF2α), are natural candidates for targeted inhibition of this pathway. Belzutifan, a highly specific and well-tolerated HIF2α inhibitor, recently received FDA approval for the treatment of nonmetastatic renal cell carcinomas, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas from patients with von Hippel-Lindau disease, who carry VHL germline mutations. Such approval is a milestone in oncology; however, the full potential, and limitations, of HIF2α inhibition in the clinic are just starting to be explored. Here we briefly recapitulate the molecular rationale for HIF2α blockade in tumors and review available preclinical and clinical data, elaborating on mutations that might be particularly sensitive to this approach. We also outline some emerging mechanisms of intrinsic and acquired resistance to HIF2α inhibitors, including acquired mutations of the gatekeeper pocket of HIF2α and its interacting partner ARNT. Lastly, we propose that the high efficacy of belzutifan observed in tumors with genetically driven hypoxia caused by VHL mutations suggests that a focus on other mutations that similarly lead to HIF2α stabilization, such as those occurring in neuroendocrine tumors with disruptions in the tricarboxylic acid cycle (SDHA/B/C/D, FH, MDH2, IDH2), HIF hydroxylases (EGLN/PHDs), and the HIF2α-encoding gene, EPAS1, are warranted.
Engineering Heart Valve Interfaces Using Melt Electrowriting: Biomimetic Design Strategies from Multi‐Modal Imaging
Authors: Michael J. Vernon, Jason Lu, Benjamin Padman, Christopher Lamb, Ross Kent, Petra Mela, Barry Doyle, Abdul Rahman Ihdayhid, Shirley Jansen, Rodney J. Dilley, Elena M. De‐Juan‐Pardo
Journal: Advanced Healthcare Materials (2022)

Interfaces within biological tissues not only connect different regions but also contribute to the overall functionality of the tissue. This is especially true in the case of the aortic heart valve. Here, melt electrowriting (MEW) is used to engineer complex, user-defined, interfaces for heart valve scaffolds. First, a multi-modal imaging investigation into the interfacial regions of the valve reveals differences in collagen orientation, density, and recruitment in previously unexplored regions including the commissure and inter-leaflet triangle. Overlapping, suturing, and continuous printing methods for interfacing MEW scaffolds are then investigated for their morphological, tensile, and flexural properties, demonstrating the superior performance of continuous interfaces. G-codes for MEW scaffolds with complex interfaces are designed and generated using a novel software and graphical user interface. Finally, a singular MEW scaffold for the interfacial region of the aortic heart valve is presented incorporating continuous interfaces, gradient porosities, variable layer numbers across regions, and tailored fiber orientations inspired by the collagen distribution and orientation from the multi-modal imaging study. The scaffold exhibits similar yield strain, hysteresis, and relaxation behavior to porcine heart valves. This work demonstrates the ability of a bioinspired approach for MEW scaffold design to address the functional complexity of biological tissues.
Distinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti–PD-1 Immunotherapy in Endometrial Carcinoma
Authors: Ryan D. Chow, Tai Michaels, Stefania Bellone, Tobias M.P. Hartwich, Elena Bonazzoli, Akiko Iwasaki, Eric Song, Alessandro D. Santin
Journal: Cancer Discovery (2022)

Mismatch repair-deficient (MMRd) cancers have varied responses to immune-checkpoint blockade (ICB). We conducted a phase II clinical trial of the PD-1 inhibitor pembrolizumab in 24 patients with MMRd endometrial cancer (NCT02899793). Patients with mutational MMRd tumors (6 patients) had higher response rates and longer survival than those with epigenetic MMRd tumors (18 patients). Mutation burden was higher in tumors with mutational MMRd compared with epigenetic MMRd; however, within each category of MMRd, mutation burden was not correlated with ICB response. Pretreatment JAK1 mutations were not associated with primary resistance to pembrolizumab. Longitudinal single-cell RNA-seq of circulating immune cells revealed contrasting modes of antitumor immunity for mutational versus epigenetic MMRd cancers. Whereas effector CD8+ T cells correlated with regression of mutational MMRd tumors, activated CD16+ NK cells were associated with ICB-responsive epigenetic MMRd tumors. These data highlight the interplay between tumor-intrinsic and tumor-extrinsic factors that influence ICB response. The molecular mechanism of MMRd is associated with response to anti-PD-1 immunotherapy in endometrial carcinoma. Tumors with epigenetic MMRd or mutational MMRd are correlated with NK cell or CD8+ T cell-driven immunity, respectively. Classifying tumors by the mechanism of MMRd may inform clinical decision-making regarding cancer immunotherapy. This article is highlighted in the In This Issue feature, p. 247.
Using Data to Improve the Management of Diabetes: The Tayside Experience
Authors: Moneeza K. Siddiqui, Christopher Hall, Scott G. Cunningham, Rory McCrimmon, Andrew Morris, Graham P. Leese, Ewan R. Pearson
Journal: Diabetes Care (2022)

Tayside is a region in the East of Scotland and forms one of nine local government regions in the country. It is home to approximately 416,000 individuals who fall under the National Health Service (NHS) Tayside health board, which provides health care services to the population. In Tayside, Scotland, a comprehensive informatics network for diabetes care and research has been established for over 25 years. This has expanded more recently to a comprehensive Scotland-wide clinical care system, Scottish Care Information - Diabetes (SCI-Diabetes). This has enabled improved diabetes screening and integrated management of diabetic retinopathy, neuropathy, nephropathy, cardiovascular health, and other comorbidities. The regional health informatics network links all of these specialized services with comprehensive laboratory testing, prescribing records, general practitioner records, and hospitalization records. Not only do patients benefit from the seamless interconnectedness of these data, but also the Tayside bioresource has enabled considerable research opportunities and the creation of biobanks. In this article we describe how health informatics has been used to improve care of people with diabetes in Tayside and Scotland and, through anonymized data linkage, our understanding of the phenotypic and genotypic etiology of diabetes and associated complications and comorbidities.
Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic <i>NF2</i> Mutations
Authors: Priscilla K. Brastianos, Erin L. Twohy, Elizabeth R. Gerstner, Timothy J. Kaufmann, A. John Iafrate, Jochen Lennerz, Suriya Jeyapalan, David E. Piccioni, Varun Monga, Camilo E. Fadul, David Schiff, Jennie W. Taylor, Sajeel A. Chowdhary, Chetan Bettegowda, George Ansstas, Macarena De La Fuente, Mark D. Anderson, Nicole Shonka, Denise Damek, Jose Carrillo, Lara J. Kunschner-Ronan, Rekha Chaudhary, Kurt A. Jaeckle, Francis M. Senecal, Thomas Kaley, Tara Morrison, Alissa A. Thomas, Mary R. Welch, Fabio Iwamoto, David Cachia, Adam L. Cohen, Shivangi Vora, Michael Knopp, Ian F. Dunn, Priya Kumthekar, Jann Sarkaria, Susan Geyer, Xiomara W. Carrero, Maria Martinez-Lage, Daniel P. Cahill, Paul D. Brown, Caterina Giannini, Sandro Santagata, Frederick G. Barker, Evanthia Galanis
Journal: Journal of Clinical Oncology (2022)

Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with
Phase Ib Study of Telisotuzumab Vedotin in Combination With Erlotinib in Patients With c-Met Protein–Expressing Non–Small-Cell Lung Cancer
Authors: D. Ross Camidge, Fabrice Barlesi, Jonathan W. Goldman, Daniel Morgensztern, Rebecca Heist, Everett Vokes, Alex Spira, Eric Angevin, Wu-Chou Su, David S. Hong, John H. Strickler, Monica Motwani, Martin Dunbar, Apurvasena Parikh, Elysa Noon, Vincent Blot, Jun Wu, Karen Kelly
Journal: Journal of Clinical Oncology (2022)

Overexpression of c-Met protein and epidermal growth factor receptor (EGFR) mutations can co-occur in non-small-cell lung cancer (NSCLC), providing strong rationale for dual targeting. Telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate targeting c-Met, has shown a tolerable safety profile and antitumor activity as monotherapy. Herein, we report the results of a phase Ib study (ClinicalTrials.gov identifier: NCT02099058) evaluating Teliso-V plus erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in patients with c-Met-positive (+) NSCLC.This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age ≥ 18 years) with c-Met+ NSCLC. Later enrollment required presence of an EGFR-activating mutation (EGFR-M+) and progression on a prior EGFR TKI. End points included safety, pharmacokinetics, objective response rate (ORR), and progression-free survival (PFS). The efficacy-evaluable population consisted of c-Met+ patients (confirmed histology [H]-score ≥ 150) who had at least one postbaseline scan; c-Met+ patients with H-scores ≥ 225 were classified as c-Met high.As of January 2020, 42 patients were enrolled (N = 36 efficacy-evaluable). Neuropathies were the most common any-grade adverse events reported, with 24 of 42 patients (57%) experiencing at least one event. The pharmacokinetic profile of Teliso-V plus erlotinib was similar to Teliso-V monotherapy. Median PFS for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8 to not reached). ORR for EGFR-M+ patients (n = 28) was 32.1%. Of EGFR-M+ patients, those who were c-Met high (n = 15) had an ORR of 52.6%. Median PFS was 6.8 months for non-T790M+ and for those whose T790M status was unknown, versus 3.7 months for T790M+.Teliso-V plus erlotinib showed encouraging antitumor activity and acceptable toxicity in EGFR TKI-pretreated patients with EGFR-M+, c-Met+ NSCLC.
Errors in Figure and in Table Titles
Authors: Manali Patel, Kristopher Kapphahn
Journal: JAMA Oncology (2022)

Chan Yeu Pu, MD, MS; Christine M. Lusk, MPH; Christine Neslund-Dudas, PhD; Shirish Gadgeel, MD; Ayman O. Soubani, MD; Ann G. Schwartz, MPH, PhD
Sweet-Talking the Distal Nephron Calcium-Sensing Receptor
Authors: Arohan R. Subramanya
Journal: Journal of the American Society of Nephrology (2022)

1Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 2Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 3VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania Correspondence: Dr. Arohan R. Subramanya, Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, S832 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. Email: [email protected] See related article, "Glucose/Fructose Delivery to the Distal Nephron Induces Activation of the Sodium-Chloride Cotransporter via Calcium-Sensing Receptor," on pages 55–72.
Antibody–Antimicrobial Conjugates for Combating Antibiotic Resistance
Authors: Luofeng Yu, Zifang Shang, Qizhe Jin, Siew Yin Chan, Weilin Hong, Nan Li, Peng Li
Journal: Advanced Healthcare Materials (2022)

Abstract As the development of new antibiotics lags far behind the emergence of drug‐resistant bacteria, alternative strategies to resolve this dilemma are urgently required. Antibody‐drug conjugate is a promising therapeutic platform to delivering cytotoxic payloads precisely to target cells for efficient disease treatment. Antibody–antimicrobial conjugates (AACs) have recently attracted considerable interest from researchers as they can target bacteria in the target sites and improve the effectiveness of drugs (i.e., reduced drug dosage and adverse effects), abating the upsurge of antimicrobial resistance. In this review, the selection and progress of three essential blocks that compose the AACs: antibodies, antimicrobial payloads, and linkers are discussed. The commonly used conjugation strategies and the latest applications of AACs in recent years are also summarized. The challenges and opportunities of this booming technology are also discussed at the end of this review.
Integrating Community Health Workers Into Care for Patients With Advanced Stages of Cancer—Fragility Index Analysis—Reply
Authors: Manali I. Patel, Kristopher Kapphahn
Journal: JAMA Oncology (2022)

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Analysis of Serious Adverse Event Reporting for Patients Enrolled in Cancer Clinical Trials During the COVID-19 Pandemic
Authors: Meera V. Ragavan, Nichole Legaspi, Alyssa LaLanne, Julian C. Hong, Eric J. Small, Hala T. Borno
Journal: JAMA Oncology (2022)

This cross-sectional study assesses whether a change occurred in reporting of serious adverse events for patients in oncology clinical trials in the US during the COVID-19 pandemic.
Clinical Trial Participation Among Older Adult Medicare Fee-for-Service Beneficiaries With Cancer
Authors: Angela K. Green, Sara M. Tabatabai, Carol Aghajanian, Ola Landgren, Gregory J. Riely, Paul Sabbatini, Peter B. Bach, Colin B. Begg, Allison Lipitz-Snyderman, Sham Mailankody
Journal: JAMA Oncology (2022)

Clinical trials play a critical role in the development of novel cancer therapies, and precise estimates of the frequency with which older adult patients with cancer participate in clinical trials are lacking.To estimate the proportion of older adult Medicare Fee-for-Service (FFS) beneficiaries with cancer who participate in interventional cancer clinical trials, using a novel population-based methodology.In this retrospective cohort study evaluating clinical trial participation among older adult patients with cancer from January 1, 2014, through June 30, 2020, claims data from Medicare FFS were linked with the ClinicalTrials.gov to determine trial participation through the unique National Clinical Trial (NCT) identifier. The proportion of patients with newly diagnosed or newly recurrent cancer in 2015 participating in an interventional clinical trial and receiving active cancer treatment from January 2014 to June 2020 was estimated. Data analysis was performed from November 18, 2020, to November 1, 2021.Patients with cancer aged 65 years or older with Medicare FFS insurance, with and without active cancer treatment.Enrollment in clinical trials among all patients with cancer 65 years and older and among patients receiving active cancer treatments as defined by the presence of at least 1 NCT identifier corresponding to an interventional cancer clinical trial in Medicare claims.Among 1 150 978 patients (mean [SD] age, 75.7 [8.4] years; 49.9% men and 50.1% women) with newly diagnosed or newly recurrent cancer in 2015, 12 028 (1.0%) patients had a billing claim with an NCT identifier indicating enrollment in an interventional cancer clinical trial between January 2014 and June 2020. In a subset of 429 343 patients with active cancer treatment, 8360 (1.9%) were enrolled in 1 or more interventional trials. Patients enrolled in a trial tended to be younger, male, a race other than Black, and residing in zip codes with high median incomes.Findings of this cohort study show that clinical trial enrollment among older adult patients with cancer remains low, with only 1.0% to 1.9% of patients with newly diagnosed or recurrent cancer in 2015 participating in an interventional cancer clinical trial as measured by the presence of NCT identifiers in Medicare claims. These data provide a contemporary estimate of trial enrollment, persistent disparities in trial participation, and only limited progress in trial access over the past 2 decades.
The study of rational framing effects needs developmental psychology
Authors: Jared Vasil
Journal: Behavioral and Brain Sciences (2022)

Abstract Experimental research is reviewed which suggests that rational framing effects influence young children's social activities according to a logic of interdependence. However, young children are unlikely to possess some of the elaborate cognitive skills argued in the Target Article to be prerequisite for rational framing effects. Understanding rational framing effects requires understanding their ontogenetic origins.